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Suppression of NF-κB signaling and NLRP3 inflammasome activation in macrophages is responsible for the amelioration of experimental murine colitis by the natural compound fraxinellone.
Toxicol Appl Pharmacol. 2014 11 15; 281(1):146-56.TA

Abstract

Inflammatory bowel disease (IBD) affects millions of people worldwide. Although the etiology of this disease is uncertain, accumulating evidence indicates a key role for the activated mucosal immune system. In the present study, we examined the effects of the natural compound fraxinellone on dextran sulfate sodium (DSS)-induced colitis in mice, an animal model that mimics IBD. Treatment with fraxinellone significantly reduced weight loss and diarrhea in mice and alleviated the macroscopic and microscopic signs of the disease. In addition, the activities of myeloperoxidase and alkaline phosphatase were markedly suppressed, while the levels of glutathione were increased in colitis tissues following fraxinellone treatment. This compound also decreased the colonic levels of interleukin (IL)-1β, IL-6, IL-18 and tumor necrosis factor (TNF)-α in a concentration-dependent manner. These effects of fraxinellone in mice with experimental colitis were attributed to its inhibition of CD11b(+) macrophage infiltration. The mRNA levels of macrophage-related molecules in the colon, including intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2), were also markedly inhibited following fraxinellone treatment. The results from in vitro assays showed that fraxinellone significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide (NO), IL-1β and IL-18 as well as the activity of iNOS in both THP-1 cells and mouse primary peritoneal macrophages. The mechanisms responsible for these effects were attributed to the inhibitory role of fraxinellone in NF-κB signaling and NLRP3 inflammasome activation. Overall, our results support fraxinellone as a novel drug candidate in the treatment of colonic inflammation.

Authors+Show Affiliations

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. Electronic address: yangsun@nju.edu.cn.State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. Electronic address: molpharm@163.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25448682

Citation

Wu, Xue-Feng, et al. "Suppression of NF-κB Signaling and NLRP3 Inflammasome Activation in Macrophages Is Responsible for the Amelioration of Experimental Murine Colitis By the Natural Compound Fraxinellone." Toxicology and Applied Pharmacology, vol. 281, no. 1, 2014, pp. 146-56.
Wu XF, Ouyang ZJ, Feng LL, et al. Suppression of NF-κB signaling and NLRP3 inflammasome activation in macrophages is responsible for the amelioration of experimental murine colitis by the natural compound fraxinellone. Toxicol Appl Pharmacol. 2014;281(1):146-56.
Wu, X. F., Ouyang, Z. J., Feng, L. L., Chen, G., Guo, W. J., Shen, Y., Wu, X. D., Sun, Y., & Xu, Q. (2014). Suppression of NF-κB signaling and NLRP3 inflammasome activation in macrophages is responsible for the amelioration of experimental murine colitis by the natural compound fraxinellone. Toxicology and Applied Pharmacology, 281(1), 146-56. https://doi.org/10.1016/j.taap.2014.10.002
Wu XF, et al. Suppression of NF-κB Signaling and NLRP3 Inflammasome Activation in Macrophages Is Responsible for the Amelioration of Experimental Murine Colitis By the Natural Compound Fraxinellone. Toxicol Appl Pharmacol. 2014 11 15;281(1):146-56. PubMed PMID: 25448682.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Suppression of NF-κB signaling and NLRP3 inflammasome activation in macrophages is responsible for the amelioration of experimental murine colitis by the natural compound fraxinellone. AU - Wu,Xue-Feng, AU - Ouyang,Zi-Jun, AU - Feng,Li-Li, AU - Chen,Gong, AU - Guo,Wen-Jie, AU - Shen,Yan, AU - Wu,Xu-Dong, AU - Sun,Yang, AU - Xu,Qiang, Y1 - 2014/10/13/ PY - 2014/09/09/received PY - 2014/09/28/revised PY - 2014/10/01/accepted PY - 2014/12/3/entrez PY - 2014/12/3/pubmed PY - 2014/12/3/medline KW - Experimental colitis KW - Fraxinellone KW - Inflammatory bowel disease KW - Macrophages KW - NF-κB KW - NLRP3 inflammasome SP - 146 EP - 56 JF - Toxicology and applied pharmacology JO - Toxicol. Appl. Pharmacol. VL - 281 IS - 1 N2 - Inflammatory bowel disease (IBD) affects millions of people worldwide. Although the etiology of this disease is uncertain, accumulating evidence indicates a key role for the activated mucosal immune system. In the present study, we examined the effects of the natural compound fraxinellone on dextran sulfate sodium (DSS)-induced colitis in mice, an animal model that mimics IBD. Treatment with fraxinellone significantly reduced weight loss and diarrhea in mice and alleviated the macroscopic and microscopic signs of the disease. In addition, the activities of myeloperoxidase and alkaline phosphatase were markedly suppressed, while the levels of glutathione were increased in colitis tissues following fraxinellone treatment. This compound also decreased the colonic levels of interleukin (IL)-1β, IL-6, IL-18 and tumor necrosis factor (TNF)-α in a concentration-dependent manner. These effects of fraxinellone in mice with experimental colitis were attributed to its inhibition of CD11b(+) macrophage infiltration. The mRNA levels of macrophage-related molecules in the colon, including intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2), were also markedly inhibited following fraxinellone treatment. The results from in vitro assays showed that fraxinellone significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide (NO), IL-1β and IL-18 as well as the activity of iNOS in both THP-1 cells and mouse primary peritoneal macrophages. The mechanisms responsible for these effects were attributed to the inhibitory role of fraxinellone in NF-κB signaling and NLRP3 inflammasome activation. Overall, our results support fraxinellone as a novel drug candidate in the treatment of colonic inflammation. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/25448682/Suppression_of_NF_κB_signaling_and_NLRP3_inflammasome_activation_in_macrophages_is_responsible_for_the_amelioration_of_experimental_murine_colitis_by_the_natural_compound_fraxinellone_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(14)00363-9 DB - PRIME DP - Unbound Medicine ER -